Adipose Tissue Of Obese Humans Research Articles

1601-P: Regulation of Circadian Rhythmicity of Human Adipose Tissue in Obesity

1601-P: Regulation of Circadian Rhythmicity of Human Adipose Tissue in Obesity

CD28-expressing δ T cells are increased in perivascular adipose tissue of hypertensive mice and in subcutaneous adipose tissue of obese humans.

γδ T-lymphocytes play a role in angiotensin II (AngII)-induced hypertension, vascular injury and T-cell infiltration in perivascular adipose tissue (PVAT) in mice. Mesenteric arteries of hypertensive mice and subcutaneous arteries from obese humans present similar remodeling. We hypothesized that γδ T-cell subtypes in mesenteric vessels with PVAT (MV/PVAT) from hypertensive mice and subcutaneous adipose tissue (SAT) from obese humans, who are prone to develop hypertension, would be similar. Mice were infused with AngII for 14 days. MV/PVAT T-cells were used for single-cell RNA-sequencing (scRNA-seq). scRNA-seq data (GSE155960) of SAT CD45 + cells from three lean and three obese women were downloaded from the Gene Expression Omnibus database. δ T-cell subclustering identified six δ T-cell subtypes. AngII increased T-cell receptor δ variable 4 ( Trdv4 ) + γδ T-effector memory cells and Cd28high δ T EM -cells, changes confirmed by flow cytometry. δ T-cell subclustering identified nine δ T-cell subtypes in human SAT. CD28 expressing δ T-cell subclustering demonstrated similar δ T-cell subpopulations in murine MV/PVAT and human SAT. Cd28+ γδ NKT EM and Cd28high δ T EM -cells increased in MV/PVAT from hypertensive mice and CD28high δ T EM -cells in SAT from obese women compared to the lean women. Similar CD28 + δ T-cells were identified in murine MV/PVAT and human SAT. CD28 high δ T EM -cells increased in MV/PVAT in hypertensive mice and in SAT from humans with obesity, a prehypertensive condition. CD28 + δ T-lymphocytes could have a pathogenic role in human hypertension associated with obesity, and could be a potential target for therapy.

Selegiline Modulates Lipid Metabolism by Activating AMPK Pathways of Epididymal White Adipose Tissues in HFD-Fed Obese Mice.

Obesity, as a major cause of many chronic diseases such as diabetes, cardiovascular disease, and cancer, is among the most serious health problems. Increased monoamine oxidase (MAO) activity has been observed in the adipose tissue of obese humans and animals. Although previous studies have already demonstrated the potential of MAO-B inhibitors as a treatment for this condition, the mechanism of their effect has been insufficiently elucidated. In this study, we investigated the anti-obesity effect of selegiline, a selective MAO-B inhibitor, using in vivo animal models. The effect was evaluated through an assessment of body energy homeostasis, glucose tolerance tests, and biochemical analysis. Pharmacological inhibition of MAO-B by selegiline was observed to reduce body weight and fat accumulation, and improved glucose metabolism without a corresponding change in food intake, in HFD-fed obese mice. We also observed that both the expression of adipogenenic markers, including C/EBPα and FABP4, and lipogenic markers such as pACC were significantly reduced in epididymal white adipose tissues (eWATs). Conversely, increased expression of lipolytic markers such as ATGL and pHSL and AMPK phosphorylation were noted. Treating obese mice with selegiline significantly increased expression levels of UCP1 and promoted eWAT browning, indicating increased energy expenditure. These results suggest that selegiline, by inhibiting MAO-B activity, is a potential anti-obesity treatment.

Distinct PD-1 hiCD4+ T helper cell populations promote CD11c+ T-bet+ B cell expansion in liver and spleen during obesity.

Abstract Obesity is associated with increased deposition of fat in ectopic tissues, such as within the liver and visceral adipose depots, including the omentum and mesentery. Increased visceral fat is an accompanying feature of the metabolic syndrome and is associated with increased end-organ damage in NAFLD. Emerging evidence implicates intrahepatic B cells in the progression of NAFLD, and increased number of proinflammatory B cells have been found in the steatotic livers of HFD-fed mice. Our preliminary studies demonstrate accumulation of inflammatory T-bet+ CD11c+ B cells in the subcutaneous adipose tissue of obese humans and perigonadal adipose tissue of mice on HFD. We now extend those findings into other sites of ectopic fat deposition to determine the obesity-related changes in T-bet+ B cell frequencies in the liver, omenta, and MAT. Flow cytometry identified increased frequencies of T-bet+ B cells in the spleen and livers, but not visceral adipose, of HFD mice. Furthermore, HFD-associated expansion of T-bet+ B cells in the spleen and liver correlated with a rise of T FHand T PHfrequencies, respectively. Future studies will determine the mechanism of tissue-specific T and B cell interactions associated with obesity-induced chronic inflammation. B.T.E. is supported by the NIH award (K12GM111726). T.H. is supported by a postdoctoral fellowship from the Swedish Research Council. This study was supported by NIH R01 AI32798-01A1 and the Voelcker Fund Young Investigator Awards (E.A.L).

Multiple Roles of Sirtuin 6 in Adipose Tissue Inflammation.

Adipose tissue (AT) inflammation is strongly associated with obesity-induced insulin resistance. When subjected to metabolic stress, adipocytes become inflamed and secrete a plethora of cytokines and chemokines, which recruit circulating immune cells to AT. Although sirtuin 6 (Sirt6) is known to control genomic stabilization, aging, and cellular metabolism, it is now understood to also play a pivotal role in the regulation of AT inflammation. Sirt6 protein levels are reduced in the AT of obese humans and animals and increased by weight loss. In this review, we summarize the potential mechanism of AT inflammation caused by impaired action of Sirt6 from the immune cells' point of view. We first describe the properties and functions of immune cells in obese AT, with an emphasis on discrete macrophage subpopulations which are central to AT inflammation. We then highlight data that links Sirt6 to functional phenotypes of AT inflammation. Importantly, we discuss in detail the effects of Sirt6 deficiency in adipocytes, macrophages, and eosinophils on insulin resistance or AT browning. In our closing perspectives, we discuss emerging issues in this field that require further investigation.

LBSUN87 Human Cidec Transgene Improves Lipid Metabolism And Protects Against High Fat-diet Induced Glucose Intolerance In Mice

Abstract CIDEC expression in adipose tissue positively correlates with insulin sensitivity in obese humans. Further, a single-nucleotide CIDEC variant (E186X) causes lipodystrophy, hypertriglyceridemia, and insulin resistance. To establish the unknown mechanistic link between CIDEC and maintenance of systemic glucose homeostasis, we generated transgenic mouse models expressing CIDEC (Ad-CIDECtg) and CIDEC E186X variant (Ad-CIDECmut) transgene specifically in the adipose tissue. Ad-CIDECtg but not Ad-CIDECmut mice were protected against high-fat diet (HFD)-induced glucose intolerance. Transcriptomics and lipidomics revealed the role of CIDEC in lipid metabolism. Serum triglycerides, cholesterol, and low-density lipoproteins were lower in HFD-fed Ad-CIDECtg mice compared to their littermate controls. Mechanistically, CIDEC regulates the enzymatic activity of ATGL via interacting with its activator, CGI-58, to reduce free fatty acid (FFA) release and lipotoxicity. We confirmed that CIDEC is indeed a vital regulator of lipolysis in adipose tissue of obese humans. Finally, treatment with recombinant CIDEC decreased triglyceride breakdown in visceral human adipose tissue. Our study unravels a central pathway whereby adipocyte-specific CIDEC plays a pivotal role in regulating adipose lipid-metabolism and whole-body glucose homeostasis. In sum, our findings identify human CIDEC as a potential 'drug' or a 'druggable' target to reverse obesity-induced lipotoxicity and glucose intolerance. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Sex-specific regulation of IL-10 production in human adipose tissue in obesity.

BackgroundObesity-associated metabolic complications display sexual dimorphism and can be impacted by cytokines. We previously showed that interleukin-10 (IL-10) was upregulated in white adipose tissue (WAT) of obese women with type 2 diabetes (T2D). Whether this pertains to men is unknown. The aim of this study was to compare the impact of obesity and T2D on WAT IL-10 levels in men versus women.MethodsPlasma and subcutaneous WAT biopsies were obtained from 108 metabolically well-characterized individuals. WAT IL10 expression/secretion and WAT-resident IL-10-secreting macrophage number were measured. Circulating sex hormone levels were correlated to WAT IL10 expression in 22 individuals and sex hormone effects on macrophage IL10 expression were investigated in vitro.ResultsObese women with T2D showed increased IL10 expression/secretion and IL-10-secreting WAT macrophage number compared to other female groups. This difference was absent in men. Non-obese women and men with T2D showed similar IL-10 levels compared to healthy controls, indicating that T2D alone does not regulate IL-10. Although WAT IL10 expression correlated with serum estrone (E1) concentrations, recombinant E1 did not affect macrophage IL10 expression in vitro. ConclusionWAT IL-10 levels are higher in women with obesity and T2D, but not in men and this effect is primarily attributed to obesity per se. This is less likely to be driven by circulating sex hormones. We propose that the WAT IL-10 might exert protective effects in obesity-associated chronic inflammation in women which could be one of the contributing factors for the decreased morbidity observed in women during obesity than men.

Human CIDEC transgene improves lipid metabolism and protects against high-fat diet–induced glucose intolerance in mice

Cell death–inducing DNA fragmentation factor-like effector C (CIDEC) expression in adipose tissue positively correlates with insulin sensitivity in obese humans. Further, E186X, a single-nucleotide CIDEC variant is associated with lipodystrophy, hypertriglyceridemia, and insulin resistance. To establish the unknown mechanistic link between CIDEC and maintenance of systemic glucose homeostasis, we generated transgenic mouse models expressing CIDEC (Ad-CIDECtg) and CIDEC E186X variant (Ad-CIDECmut) transgene specifically in the adipose tissue. We found that Ad-CIDECtg but not Ad-CIDECmut mice were protected against high-fat diet-induced glucose intolerance. Furthermore, we revealed the role of CIDEC in lipid metabolism using transcriptomics and lipidomics. Serum triglycerides, cholesterol, and low-density lipoproteins were lower in high-fat diet-fed Ad-CIDECtg mice compared to their littermate controls. Mechanistically, we demonstrated that CIDEC regulates the enzymatic activity of adipose triglyceride lipase via interacting with its activator, CGI-58, to reduce free fatty acid release and lipotoxicity. In addition, we confirmed that CIDEC is indeed a vital regulator of lipolysis in adipose tissue of obese humans, and treatment with recombinant CIDEC decreased triglyceride breakdown in visceral human adipose tissue. Our study unravels a central pathway whereby adipocyte-specific CIDEC plays a pivotal role in regulating adipose lipid metabolism and whole-body glucose homeostasis. In summary, our findings identify human CIDEC as a potential ‘drug’ or a ‘druggable’ target to reverse obesity-induced lipotoxicity and glucose intolerance.

Abstract P3128: Obesogenic Diet Promotes Endothelial-to-Mesenchymal Transition In Adipose Tissue

Vascular dysfunction and chronic inflammation are characteristics of obesity-induced adipose tissue dysfunction. Proinflammatory cytokines can drive Endothelial-to-Mesenchymal Transition (EndoMT), where endothelial cells transition into mesenchymal-like interstitial cells that leave the vascular wall and promote tissue inflammation and fibrosis. In this study, we aimed to determine whether obesogenic diet can promote EndoMT in adipose tissue. EndoMT was assessed in 1) transgenic endothelial cell lineage-tracing mice subjected to High-Fat/High-Sucrose (HF/HS) diet, 2) available single cell RNA sequencing datasets from human obese adipose tissue, and 3) cell culture models using primary human adipose-derived endothelial cells. In lineage-tracing mice, obesogenic diet induced EndoMT in a time-dependent manner at 13, 26, and 52 weeks on HF/HS diet in both subcutaneous and visceral adipose tissue. Interestingly, rate of EndoMT was greater in visceral compared to subcutaneous adipose tissue. After 52-weeks on HF/HS diet, EndoMT cells in visceral adipose tissue upregulate inflammatory response and TGF-Beta signaling transcriptional pathways compared to endothelial cells in the same adipose tissue depot. Initiation of EndoMT was also found in single cell RNA sequencing datasets of stromal cells from human obese adipose tissue, indicated by endothelial cells in these datasets containing sub-clusters with reduced Pecam1 and increased Acta2 expression. Finally, the capacity for EndoMT in primary human adipose-derived endothelial cells was validated by bulk RNA sequencing after treatment with proinflammatory cytokines (TNF-Alpha, IFN-Gamma, TGF-Beta1), confirming decreased expression of endothelial cell genes and increased expression of genes associated with EndoMT, inflammatory response, and TGF-Beta signaling. Together, these clinical and experimental findings indicate that chronic obesity can promote EndoMT in adipose endothelial cells.

Diet-induced obesity promotes CD11c+ T-bet+ B cell expansion in liver and adipose tissue

Abstract Immune cells are increasingly appreciated to play a role in inflammation in adipose and hepatic tissue during obesity and may contribute to the development of non-alcoholic fatty liver disease (NAFLD). Both invariant Natural Killer T (iNKT) cells and B cells are enriched in the liver and adipose tissues of humans and mice, but the degree and nature of their influence in the development of NAFLD remains unclear. iNKT cells interact with B cells in many contexts, including during the chronic inflammation associated with autoimmune disease and infection, so it is likely they interact during obesity. Emerging evidence implicates intrahepatic B cells in the progression of human NAFLD, and proinflammatory B cells increase in the steatotic livers of HFD-fed mice. Our preliminary studies demonstrate an iNKT cell-dependent expansion of inflammatory CD11c+ T-bet+ B cells in the subcutaneous adipose tissue of obese humans and perigonadal adipose tissue of obese mice. We now extend those findings to other iNKT cell-rich fatty depots. Flow cytometry identified increased frequencies of T-bet+ B cells in the livers, but not the omenta or mesenteric adipose tissue, of obese mice. In parallel to the in vivo studies, in vitro co-cultures revealed that iNKT cells are sufficient to mediate expansion of T-bet+ B cells. Ongoing experiments will examine the potential role and mechanism of iNKT cells in mediating hepatic Tbet+ B cell expansion. Characterization of the specific contribution of immune inflammation in the progression NAFLD to NASH will allow for the design of successful therapeutic interventions for this increasingly frequent public health problem. Funding support from NIH K12GM111726 (BTE), NIH TL1 TR002647 (TS), Swedish Research Council (TH), and NIH R01 AI32798-01A1 (EAL).

Neutrophil Extracellular Traps Contribute to Perivascular Adipose Tissue Dysfunction in High‐Fat Diet Obese Mice

BackgroundObesity triggers functional changes in the perivascular adipose tissue (PVAT), favoring the release of vasoconstrictor factors and the activation of contractile mechanisms in vascular smooth muscle cells. In the PVAT of obese individuals, there is infiltration of immune cells, including neutrophils. A neutrophil defense mechanism is the formation of neutrophil extracellular traps (NETs), a cytotoxic framework that allows maintenance and expansion of inflammatory processes. We hypothesize that PVAT dysfunction in obese mice is due to increased neutrophil infiltration, NETs formation and inflammation.MethodsSix weeks‐old male Balb/C mice received control (CD) or high fat diet (HFD) for 18 weeks. Vascular function was assessed in endothelium‐intact mesenteric arteries in the presence or absence of PVAT. Mice were treated with DNAse type 1 (10 mg/kg for 14 days, every other day). Molecular mechanisms were investigated. Experiments were approved by the Ethics Committee on Animal Research of the Ribeirao Preto Medical School, University of Sao Paulo (protocol nº 209/2016)ResultsValues are expressed relatively to the contraction triggered by 120 mM KCl [Emax (% KCl)]. In Balb/C mice, the PVAT decreased the contractile response in control arteries [Control PVAT (‐): 123.2±8.1 n=6; Control PVAT (+): 64.4±4.0 n=6]. However, HFD promoted partial loss of PVAT anti‐contractile effect [HFD PVAT (‐): 127.9±6.9 n=6; HFD PVAT (+): 98.3±7.4 n=6]. In PVAT of obese mice there was a greater amount of neutrophils, compared to PVAT from control mice [Control: 8.0% n=5; HFD: 18.9% n=5]. In PVAT of obese mice there was greater formation of NETs, and production of interleukin 6 (IL‐6), compared to PVAT from control mice [NETs in pg/ml – Control: 30.5±2.7 n=6; HFD: 71.4±3.2 n=6; IL‐6 in pg/100 mg of PVAT – Control: 45.6±1.9 n=6; HFD: 98.4±3.1 n=6]. DNAse treatment reduced the formation of NETs and IL‐6 in the PVAT of obese mice [NETs in pg/ml – HFD+DNAse: 18.3±1.2 n=6; IL‐6 in pg/100 mg of PVAT – HFD: 48.1±3.4 n=6]. DNAse treatment restored PVAT anticontractile function in obese mice [HFD+DNAse PVAT (+): 71.3±7.4 n=6]. Adipose tissue of obese humans exhibited greater formation of NETs and production of IL‐6 compared to adipose tissue of eutrophic humans [NETs in pg/ml – Eutrophic: 20.5±3.7 n=7; Obese: 79.2±1.3 n=7; IL‐6 in pg/100 mg of adipose tissue – Eutrophic: 9.7±2.9 n=7; Obese: 27.7±2.6 n=7].ConclusionThese results indicate that, in obesity, there is a greater neutrophils infiltration in the PVAT and, consequently, greater formation of NETs and inflammation, events that contribute to PVAT dysfunction.

Human CD206+ macrophages associate with diabetes and adipose tissue lymphoid clusters.

Increased adipose tissue macrophages (ATMs) correlate with metabolic dysfunction in humans and are causal in development of insulin resistance in mice. Recent bulk and single-cell transcriptomics studies reveal a wide spectrum of gene expression signatures possible for macrophages that depends on context, but the signatures of human ATM subtypes are not well defined in obesity and diabetes. We profiled 3 prominent ATM subtypes from human adipose tissue in obesity and determined their relationship to type 2 diabetes. Visceral adipose tissue (VAT) and s.c. adipose tissue (SAT) samples were collected from diabetic and nondiabetic obese participants to evaluate cellular content and gene expression. VAT CD206+CD11c− ATMs were increased in diabetic participants, were scavenger receptor–rich with low intracellular lipids, secreted proinflammatory cytokines, and diverged significantly from 2 CD11c+ ATM subtypes, which were lipid-laden, were lipid antigen presenting, and overlapped with monocyte signatures. Furthermore, diabetic VAT was enriched for CD206+CD11c− ATM and inflammatory signatures, scavenger receptors, and MHC II antigen presentation genes. VAT immunostaining found CD206+CD11c– ATMs concentrated in vascularized lymphoid clusters adjacent to CD206–CD11c+ ATMs, while CD206+CD11c+ were distributed between adipocytes. Our results show ATM subtype–specific profiles that uniquely contribute to the phenotypic variation in obesity.

Obesity Accelerates Age Defects in Human B Cells and Induces Autoimmunity.

Aging is associated with systemic inflammation and decreased production of protective antibodies while the production of autoimmune antibodies is increased. Our results have shown that the human obese adipose tissue (AT), which increases in size with aging, contributes to systemic and B cell intrinsic inflammation, reduced protective and increased pathogenic B cell responses leading to increased secretion of autoimmune antibodies.With this R56 funding, we have been able to investigate the cellular and molecular mechanisms by which the human obese AT induces intrinsic B cell inflammation and dysfunctional B cell responses, stimulates the secretion of autoimmune antibodies, whose specificity has been characterized, and engages different AT cell types in antigen presentation pathways to allow secretion of these autoimmune antibodies. Briefly, immune cells are recruited to the AT by chemokines released by both non-immune (adipocytes) and by resident and infiltrating immune cells. We have identified several mechanisms responsible for the release of “self” antigens, and we have shown that reduced oxygen availability and hypoxia, cell cytotoxicity and DNA damage induce cell death and lead to further release of pro-inflammatory cytokines, “self” protein antigens, cell-free DNA and lipids. We have also identified different antigen presenting cells in the AT, responsible for the activation of pathogenic B cells, class switch and secretion of autoimmune IgG antibodies. The experiments performed have allowed the discovery of novel mechanisms for pathogenic responses and the identification of pathways to target in order to promote better humoral immunity during aging.

Obesity Inhibits Angiogenesis Through TWIST1-SLIT2 Signaling.

Angiogenesis is required for functional adipose tissue maintenance, remodeling, and expansion. Physiologically balanced adipogenesis and angiogenesis are inhibited in subcutaneous adipose tissue in obese humans. However, the mechanism by which angiogenesis is inhibited in obese adipose tissue is not fully understood. Transcription factor TWIST1 controls angiogenesis and vascular function. TWIST1 expression is lower in obese human adipose tissues. Here, we have demonstrated that angiogenesis is inhibited in endothelial cells (ECs) isolated from adipose tissues of obese humans through TWIST1-SLIT2 signaling. The levels of TWIST1 and SLIT2 are lower in ECs isolated from obese human adipose tissues compared to those from lean tissues. Knockdown of TWIST1 in lean human adipose ECs decreases, while overexpression of TWIST1 in obese adipose ECs restores SLIT2 expression. DNA synthesis and cell migration are inhibited in obese adipose ECs and the effects are restored by TWIST1 overexpression. Obese adipose ECs also inhibit blood vessel formation in the gel subcutaneously implanted in mice, while these effects are restored when gels are mixed with SLIT2 or supplemented with ECs overexpressing TWIST1. These findings suggest that obesity impairs adipose tissue angiogenesis through TWIST1-SLIT2 signaling.

The miR-182-5p/FGF21/acetylcholine axis mediates the crosstalk between adipocytes and macrophages to promote beige fat thermogenesis.

A dynamically regulated microenvironment, which is mediated by crosstalk between adipocytes and neighboring cells, is critical for adipose tissue homeostasis and function. However, information on key molecules and/or signaling pathways regulating the crosstalk remains limited. In this study, we identify adipocyte miRNA-182-5p (miR-182-5p) as a crucial antiobesity molecule that stimulated beige fat thermogenesis by promoting the crosstalk between adipocytes and macrophages. miR-182-5p was highly enriched in thermogenic adipocytes, and its expression was markedly stimulated by cold exposure in mice. In contrast, miR-182-5p expression was significantly reduced in adipose tissues of obese humans and mice. Knockout of miR-185-5p decreased cold-induced beige fat thermogenesis whereas overexpression of miR-185-5p increased beiging and thermogenesis in mice. Mechanistically, miR-182-5p promoted FGF21 expression and secretion in adipocytes by suppressing nuclear receptor subfamily 1 group D member 1 (Nr1d1) at 5′-UTR, which in turn stimulates acetylcholine synthesis and release in macrophages. Increased acetylcholine expression activated the nicotine acetylcholine receptor in adipocytes, which stimulated PKA signaling and consequent thermogenic gene expression. Our study reveals a key role of the miR-182-5p/FGF21/acetylcholine/acetylcholine receptor axis that mediates the crosstalk between adipocytes and macrophages to promote beige fat thermogenesis. Activation of the miR-182-5p–induced signaling pathway in adipose tissue may be an effective approach to ameliorate obesity and associated metabolic diseases.

AGE/RAGE/DIAPH1 axis is associated with immunometabolic markers and risk of insulin resistance in subcutaneous but not omental adipose tissue in human obesity

Background/objectivesThe incidence of obesity continues to increase worldwide and while the underlying pathogenesis remains largely unknown, nutrient excess, manifested by “Westernization” of the diet and reduced physical activity have been proposed as key contributing factors. Western-style diets, in addition to higher caloric load, are characterized by excess of advanced glycation end products (AGEs), which have been linked to the pathophysiology of obesity and related cardiometabolic disorders. AGEs can be “trapped” in adipose tissue, even in the absence of diabetes, in part due to higher expression of the receptor for AGEs (RAGE) and/or decreased detoxification by the endogenous glyoxalase (GLO) system, where they may promote insulin resistance. It is unknown whether the expression levels of genes linked to the RAGE axis, including AGER (the gene encoding RAGE), Diaphanous 1 (DIAPH1), the cytoplasmic domain binding partner of RAGE that contributes to RAGE signaling, and GLO1 are differentially regulated by the degree of obesity and/or how these relate to inflammatory and adipocyte markers and their metabolic consequences.Subjects/methodsWe sought to answer this question by analyzing gene expression patterns of markers of the AGE/RAGE/DIAPH1 signaling axis in abdominal subcutaneous (SAT) and omental (OAT) adipose tissue from obese and morbidly obese subjects.ResultsIn SAT, but not OAT, expression of AGER was significantly correlated with that of DIAPH1 (n = 16; hat beta = 0.719, [0.260, 1.177]; q = 0.008) and GLO1 (n = 16; hat beta = 0.773, [0.364, 1.182]; q = 0.004). Furthermore, in SAT, but not OAT, regression analyses revealed that the expression pattern of genes in the AGE/RAGE/DIAPH1 axis is strongly and positively associated with that of inflammatory and adipogenic markers. Remarkably, particularly in SAT, not OAT, the expression of AGER positively and significantly correlated with HOMA-IR (n = 14; hat beta = 0.794, [0.338, 1.249]; q = 0.018).ConclusionsThese observations suggest associations of the AGE/RAGE/DIAPH1 axis in the immunometabolic pathophysiology of obesity and insulin resistance, driven, at least in part, through expression and activity of this axis in SAT.

Tbet+ B cells facilitate iNKT cell expansion in murine liver and omentum during obesity

Abstract Obesity is a burgeoning public health crisis, responsible for increasing chronic systemic inflammation which leads to metabolic disease in humans and mice. Understanding the contribution of immune inflammation to metabolic disease is critical for designing effective therapeutic interventions. Invariant Natural Killer T (iNKT) cells are enriched in the adipose tissue, liver, and omenta of both humans and mice, but their frequency is reduced in adipose during obesity. iNKT cells negatively regulate or positively activate other immune cells, including B cells, depending on the immunologic context. Adipose B regulatory cells protect against inflammation, but they are not the only subset of B cells in adipose tissue. Our preliminary studies find increased frequencies of inflammatory Tbet+ B cells in adipose tissue of obese humans and mice which correlates with weight gain in mice and increasing BMI in humans. We now extend those findings to consider iNKT cell interaction with B cells during obesity in the adipose, liver, and omental tissues. Flow cytometry confirmed iNKT cell-dependent expansion of Tbet+ CD11c+ B cells in adipose tissue of obese mice. Interestingly, similar expansion was not observed in liver or omental tissue from the same obese mice. Instead, the livers and omenta of obese mice demonstrated significant increases in iNKT cell frequency compared with lean mice. In contrast to the adipose tissue, the increase in liver and omental iNKT cells during obesity was missing in mice genetically deficient in Tbet+ B cells. Thus, we find that iNKT cell-dependent expansion of Tbet+ CD11c+ B cells within adipose tissue of obese mice is counter-balanced by a reciprocal Tbet+ B cell-dependent expansion of iNKT cells in liver and omentum.

Adipocyte Oncostatin Receptor Regulates Adipose Tissue Homeostasis and Inflammation.

Adipocytes are the largest cell type in terms of volume, but not number, in adipose tissue. Adipocytes are prominent contributors to systemic metabolic health. Obesity, defined by excess adipose tissue (AT), is recognized as a low-grade chronic inflammatory state. Cytokines are inflammatory mediators that are produced in adipose tissue (AT) and function in both AT homeostatic as well as pathological conditions. AT inflammation is associated with systemic metabolic dysfunction and obesity-associated infiltration and proliferation of immune cells occurs in a variety of fat depots in mice and humans. AT immune cells secrete a variety of chemokines and cytokines that act in a paracrine manner on adjacent adipocytes. TNFα, IL-6, and MCP-1, are well studied mediators of AT inflammation. Oncostatin M (OSM) is another proinflammatory cytokine that is elevated in AT in human obesity, and its specific receptor (OSMRβ) is also induced in conditions of obesity and insulin resistance. OSM production and paracrine signaling in AT regulates adipogenesis and the functions of AT. This review summarizes the roles of the oncostatin M receptor (OSMRβ) as a modulator of adipocyte development and function its contributions to immunological adaptations in AT in metabolic disease states.

Carbonyl reductase 1 amplifies glucocorticoid action in adipose tissue and impairs glucose tolerance in lean mice

ObjectiveCarbonyl reductase 1 (Cbr1), a recently discovered contributor to tissue glucocorticoid metabolism converting corticosterone to 20β-dihydrocorticosterone (20β-DHB), is upregulated in adipose tissue of obese humans and mice and may contribute to cardiometabolic complications of obesity. This study tested the hypothesis that Cbr1-mediated glucocorticoid metabolism influences glucocorticoid and mineralocorticoid receptor activation in adipose tissue and impacts glucose homeostasis in lean and obese states. MethodsThe actions of 20β-DHB on corticosteroid receptors in adipose tissue were investigated first using a combination of in silico, in vitro, and transcriptomic techniques and then in vivo administration in combination with receptor antagonists. Mice lacking one Cbr1 allele and mice overexpressing Cbr1 in their adipose tissue underwent metabolic phenotyping before and after induction of obesity with high-fat feeding. Results20β-DHB activated both the glucocorticoid and mineralocorticoid receptor in adipose tissue and systemic administration to wild-type mice induced glucose intolerance, an effect that was ameliorated by both glucocorticoid and mineralocorticoid receptor antagonism. Cbr1 haploinsufficient lean male mice had lower fasting glucose and improved glucose tolerance compared with littermate controls, a difference that was abolished by administration of 20β-DHB and absent in female mice with higher baseline adipose 20β-DHB concentrations than male mice. Conversely, overexpression of Cbr1 in adipose tissue resulted in worsened glucose tolerance and higher fasting glucose in lean male and female mice. However, neither Cbr1 haploinsfficiency nor adipose overexpression affected glucose dyshomeostasis induced by high-fat feeding. ConclusionsCarbonyl reductase 1 is a novel regulator of glucocorticoid and mineralocorticoid receptor activation in adipose tissue that influences glucose homeostasis in lean mice.

Adipocyte-derived extracellular vesicles regulate survival and function of pancreatic β cells.

Extracellular vesicles (EVs) are implicated in the crosstalk between adipocytes and other metabolic organs, and an altered biological cargo has been observed in EVs from human obese adipose tissue (AT). Yet, the role of adipocyte-derived EVs in pancreatic β cells remains to be determined. Here, we explored the effects of EVs released from adipocytes isolated from both rodents and humans and human AT explants on survival and function of pancreatic β cells and human pancreatic islets. EVs from healthy 3T3-L1 adipocytes increased survival and proliferation and promoted insulin secretion in INS-1E β cells and human pancreatic islets, both those untreated or exposed to cytokines or glucolipotoxicity, whereas EVs from inflamed adipocytes caused β cell death and dysfunction. Human lean adipocyte-derived EVs produced similar beneficial effects, whereas EVs from obese AT explants were harmful for human EndoC-βH3 β cells. We observed differential expression of miRNAs in EVs from healthy and inflamed adipocytes, as well as alteration in signaling pathways and expression of β cell genes, adipokines, and cytokines in recipient β cells. These in vitro results suggest that, depending on the physiopathological state of AT, adipocyte-derived EVs may influence β cell fate and function.